KR20200088945A - benzo[b][1,4]oxazepin derivatives and pharmaceutical composition for use in preventing or treating kinase-related disease - Google Patents

Abstract

The present invention relates to a benzo[b][1,4]oxazepine derivative represented by the following chemical formula 1, and a pharmaceutical composition for treating kinase-related diseases including the same as an active ingredient. The benzo[b][1,4]oxazepine derivative according to one aspect shows a high activity of inhibiting at least one kinase selected from the group consisting of ABL1, ABL2, AURKB, BRK, CDK11, CDK8, CDK9, CDKL2, CIT, DDR1, FLT3, FLT3, HIPK4, HUNK, JAK3, KIT, LOK, LTK, MET, MET, MLK2, MUSK, MYO3A, PAK3, PCTK3, PDGFRA, PDGFRB, RIPK1, TIE1 and ZAK, and thus can be used for treating kinase-related diseases.

Description

{Benzo[b][1,4]oxazepin derivatives and pharmaceutical composition for use in preventing or treating kinase- related disease}

Benzo[b][1,4] oxazepine derivatives and pharmaceutical compositions for treating kinase-related diseases comprising the same as an active ingredient.

Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxy group of proteins tyrosine, serine and threonine, and is responsible for the metabolism, gene expression, cell growth, differentiation, and cell division of cells. It plays an important role in signal transmission (Non-Patent Document 1, Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033). Protein kinases are classified into tyrosine protein kinase and serine/threonine kinase, of which about 90 or more are tyrosine kinase.

Protein kinase is a molecular switch that must smoothly regulate the transition between active and inactive states in cells. If the metastasis between the active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated, leading to uncontrollable cell division and proliferation. In addition, abnormal activation by gene mutation, amplification, and overexpression of protein kinase is related to the development and progression of various tumors, and thus plays a decisive role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer. Examples of related kinases include ABL1, ABL2, BRAF, CDK11, CDK8, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB, RAF1, RIPK1, and the like.

One embodiment of a protein kinase, receptor-interacting protein-1 (RIP1) kinase, is a multifunctional signal transducer involved in mediating NF-κB activation, apoptosis and/or necroptosis.

In particular, RIP1 kinase activity is known to be critically involved in the mediation of necroptosis, a caspase-independent pathway of necrotic cell death (Non-Patent Document 2, Holler et al., Nat Immunol 2000) ; 1: 489-495; Non-Patent Document 3, Degterev et al., Nat Chem Biol 2008; 4: 313-321).

Therefore, if RIP1 kinase activity can be effectively inhibited, cell protection is possible under apoptosis-inducing conditions by tumor necrosis factor-alpha (TNF-α), thereby blocking necroptosis. There will be.

It has been reported that necroptosis mediated by the RIP1 kinase is associated with various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, and cancer.

First, RIP3 knockout mice designed to completely block RIP1-mediated programmed necrosis are inflammatory bowel disease (including ulcerative colitis and Crohn's disease) (Non-Patent Document 4, (2011) Nature 477, 330-334), Psoriasis (Psoriasis) ) (Non-Patent Document 5, (2011) Immunity 35, 572-582), Retinal-Peel-Induced Photoreceptor Necrosis (Non-Patent Document 6, (2010) PNAS 107, 21695-21700), Retinitis pigmentosa ) (Non-patent document 7, (2012) Proc . Natl. Acad . Sci . , 109:36, 14598-14603), cerulein-induced acute pancreatitis (non-patent document 8, (2009) Cell 137, 1100-1111 ) And sepsis/systemic inflammatory response syndrome (SIRS) (Non-Patent Document 9, (2011) Immunity 35, 908-918), so certain compounds are responsible for RIP1 kinase-mediated necrosis. If blocked, the compound is likely to be developed as a treatment for inflammatory diseases.

In addition, RIP1 kinase has been known to mediate microglial response in Alzheimer's disease (Non-Patent Document 10, PNAS October 10, 2017. 114 (41) E8788-E8797), so specific compounds are RIP1 If it can effectively inhibit activity by targeting kinase, the compound can include Downs syndrome, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, proximal lateral sclerosis, stroke, stroke, including Alzheimer's disease It may also be developed as a treatment for degenerative brain disease (ie, degenerative neurological disease) such as mild cognitive impairment.

Furthermore, RIP1 kinase regulates the production of tumor necrosis factor-alpha (TNF-α), and the TNF-α is involved in cell death and inflammatory mediation in numerous diseases such as rheumatoid arthritis and cancer. Since it is known that it is a pro-inflammatory cytokine involved (Non-Patent Document 11, Cell Death and Disease (2012) 3, e320), if a specific compound can effectively inhibit activity by targeting RIP1 kinase, the compound is rheumatoid arthritis ( Rheumatoid arthritis, including rheumatoid polymyalgia, ankylosing spondylitis, motor neurone disease, such as autoimmune diseases, or cancer, may also be developed as a treatment.

In addition, RIP1 kinase has been known to induce macrophage-mediated adaptive immune tolerance in pancreatic cancer (Non-Patent Document 12, Cancer Cell 34, 757-774, November 12 , 2018). More specifically, RIP1 inhibition in TAMs results in cytotoxic T cell activation and T helper cell differentiation for mixed Th1/Th17 phenotypes, resulting in tumor immunity in organ type models of mouse and human PDA. It is disclosed to induce.

Thus, targeting RIP1 works synergistically with PD-1 and inducible co-stimulator based immunotherapy, so it can be seen that RIP1 is a checkpoint kinase that governs tumor immunity.

That is, the compound capable of effectively inhibiting the protein kinase activity including RIP1 is likely to be developed as a therapeutic agent for various diseases such as inflammatory diseases, degenerative brain diseases, autoimmune diseases, cancer, etc. Development is required.

The objective in one aspect of the present invention is to show excellent inhibitory activity against various kinase, a novel structure of benzo[b][1,4]oxazepine derivatives having a therapeutic effect on kinase-related diseases, stereoisomers thereof, its It provides a hydrate, or a pharmaceutically acceptable salt thereof.

The object in another aspect of the present invention is the prevention of kinase-related diseases containing the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable salts thereof as an active ingredient. Or to provide a pharmaceutical composition for treatment.

In another aspect of the present invention, the object of the kinase-related disease is that the benzo[b][1,4]oxazepine derivative, its stereoisomer, its hydrate, or its pharmaceutically acceptable salt is contained as an active ingredient. It is to provide a health functional food composition for prevention or improvement.

An object of another aspect of the present invention is to provide the benzo[b][1,4]oxazepine derivative, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof to a subject in need thereof. It provides a method for treating a kinase-related disease, comprising the step of administering.

An object in another aspect of the present invention, for use in the prevention or treatment of kinase-related diseases, the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable thereof It is to provide possible salts.

An object in another aspect of the present invention is a benzo[b][1,4]oxazepine derivative, a stereoisomer thereof, for use in the manufacture of a medicament for use in the prevention or treatment of kinase-related diseases. It provides a use of a hydrate or a pharmaceutically acceptable salt thereof.

In order to achieve the above object,

One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

X is hydrogen or halogen;

P is an integer of 0 or 1;

E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

E ² is =CA ² -, or =N-, and A ² is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

E ³ is =CA ³ -, or =N-, and A ³ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

R ¹ is hydrogen, C _1-10 straight or branched chain alkyl, or C _3-8 cycloalkyl;

G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, C _1-10 linear or branched alkoxycarbonyl, amino, or halogen; And

G ² is =CM ² -, or =N-, and M ² is hydrogen, C _1-10 straight or branched chain alkoxycarbonyl, amino, halogen, C _1-10 straight or branched chain alkyl, or C _1-10 linear or branched alkoxy).

Another aspect of the present invention is a kinase-related disease comprising the benzo[b][1,4]oxazepine derivative represented by Formula 1, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of.

Another aspect of the present invention relates to a kinase containing an benzo[b][1,4]oxazepine derivative represented by Chemical Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Provides a health functional food composition for preventing or improving disease.

Another aspect of the present invention is the step of administering the benzo[b][1,4]oxazepine derivative, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof It provides a method for treating a kinase-related disease, including.

Another aspect of the present invention, for use in the prevention or treatment of kinase-related diseases, the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable salts thereof to provide.

Another aspect of the present invention, for use in the manufacture of a medicament for use in the prevention or treatment of kinase-related diseases, the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, Or the use of a pharmaceutically acceptable salt thereof.

The benzo[b][1,4]oxazepine derivatives provided in one aspect of the present invention are ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK , MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1, PIKFYVE, PLK4, RIPK1, RIPK5, TRKA, exhibits excellent inhibitory activity against one or more kinases selected from the group consisting of TRK and kinase-related diseases It can be used as a therapeutic agent.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

(In the formula 1,

X is hydrogen or halogen;

P is an integer of 0 or 1;

E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

E ² is =CA ² -, or =N-, and A ² is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

E ³ is =CA ³ -, or =N-, and A ³ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;

R ¹ is hydrogen, C _1-10 straight or branched chain alkyl, or C _3-8 cycloalkyl;

G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, C _1-10 linear or branched alkoxycarbonyl, amino, or halogen; And

G ² is =CM ² -, or =N-, and M ² is hydrogen, C _1-10 straight or branched chain alkoxycarbonyl, amino, halogen, C _1-10 straight or branched chain alkyl, or C _1-10 linear or branched alkoxy).

On the other side,

X is hydrogen or halogen;

P is an integer of 0 or 1;

E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;

E ² is =CA ² -, or =N-, and A ² is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;

E ³ is =CA ³ -, or =N-, and A ³ is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;

R ¹ is hydrogen, C _1-5 straight or branched chain alkyl, or C _3-5 cycloalkyl;

G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, C _1-5 linear or branched alkoxycarbonyl, amino, or halogen; And

G ² is =CM ² -, or =N-, and M ² is hydrogen, C _1-5 linear or branched alkoxycarbonyl, amino, halogen, C _1-5 linear or branched alkyl, or C _1-5 may be a straight or branched chain alkoxy.

On the other side,

X is hydrogen, or -F;

P is an integer of 0 or 1;

E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, -CH ₃ , or -F;

E ² is =CA ² -, or =N-, and A ² is hydrogen;

E ³ is =CA ³ -, or =N-, and A ³ is hydrogen;

R ¹ is —CH ₃ , —CH ₂ CH ₃ , or cyclopropyl;

G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, methoxycarbonyl, amino, or halogen; And

The G ² is =CM ² -, or =N-, and the M ² may be hydrogen, methoxycarbonyl, amino, halogen, -CH ₃ , or -OCH ₃ .

On the other side,

The compound represented by Chemical Formula 1 may be any one compound selected from the following compound group.

(1) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;

(2) (R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;

(3) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;

(4) (R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;

(5) (S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate;

(6) (R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate;

(7) (S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate;

(8) (R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate;

(9) Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate;

(10) Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate;

(11) (R)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(12) (S)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(13) (R)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(14) (S)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(15) (R)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(16) (S)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(17) Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate;

(18) Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate;

(19) (R)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(20) (S)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(21) (R)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(22) (S)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(23) (R)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(24) (S)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(25) (S)-1-(5,7-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(26) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(7-methoxy-5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(27) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)urea;

(28) (S)-1-(5-cyclopropyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;

(29) (S)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(30) (R)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(31) (S)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(32) (R)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(33) (S)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4 -Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(34) (R)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4 -Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(35) (S)-1-(2-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(36) (R)-1-(2-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(37) (S)-1-(5-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(38) (R)-1-(5-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(39) (S)-1-(4-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(40) (R)-1-(4-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;

(41) (S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trifluoroacetate;

(42) (R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trifluoroacetate;

(43) (S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepin-3-yl)benzamide; And

(44) (R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepin-3-yl)benzamide.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from The types of pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a derivative of Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and a precipitate formed by adding an organic acid or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Furthermore, the present invention includes all of the compounds represented by Formula 1 and pharmaceutically acceptable salts thereof, as well as solvates, optical isomers, and hydrates that can be prepared therefrom.

In the compound represented by Formula 1, p is an integer of 1, as shown in Scheme 1 below,

Preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2 (step 1);

Preparing a compound represented by Formula 4 from the compound represented by Formula 3 prepared in Step 1 (Step 2);

Preparing a compound represented by formula 6 by reacting the compound represented by formula 4 and the compound represented by formula 5 prepared in step 2 (step 3); And

Preparing a compound represented by Chemical Formula 1'by reacting the compound represented by Chemical Formula 6 prepared in Step 3 with a compound represented by 1,1'-carbonyldiimidazole and Chemical Formula 7 (Step 4); It can be manufactured through.

[Scheme 1]

(In Scheme 1 above,

X, R ¹ , E ¹ , E ² , E ³ , G ¹ and G ² are as defined in Formula 1 above;

The PG is a protecting group,

In one aspect, the protecting group may be trimethylsilyl (TMS); And

X ¹ and X ² are independently halogen).

Hereinafter, a method for preparing the compound represented by Chemical Formula 1 will be described in detail step by step.

In the method for preparing a compound represented by Chemical Formula 1, step 1 is a step of preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2. More specifically, in a position where X ¹ of the compound represented by Formula 2 is bonded, a protecting group is substituted with acetylene substituted at the terminal, and in one embodiment, trimethylsilylacetylene is substituted to prepare a compound represented by Formula 3 It is a step. The reaction solvent is not particularly limited, but acetonitrile or the like can be used, and the reaction temperature can be carried out in a range of 70 to 90°C.

In the method for preparing a compound represented by Formula 1, step 2 is a step of preparing a compound represented by Formula 4 from the compound represented by Formula 3 prepared in Step 1. In this step, the removal of the protecting group may be performed by employing a method known as a removing method of the protecting group without limitation, depending on the type of the protecting group introduced. If the protecting group introduced as one specific example is trimethylsilyl (TMS), trimethylsilyl (TMS) may be removed by treating potassium carbonate under a methanol solvent.

In the method for preparing a compound represented by Formula 1, step 3 is a step of preparing a compound represented by Formula 6 by reacting the compound represented by Formula 4 and the compound represented by Formula 5 prepared in Step 2 to be. At this time, the reaction can be carried out in ethyl acetate, the reaction temperature can be carried out in the range of 30 to 70 ℃. The reaction time is not particularly limited, but may be performed for 1 hour to 3 hours.

In the method for preparing the compound represented by Chemical Formula 1, step 4 reacts the compound represented by Chemical Formula 6 prepared in Step 3 with the compound represented by 1,1′-carbonyldiimidazole and Chemical Formula 7, This is a step for preparing a compound represented by Formula 1'. In this step, the compound represented by Chemical Formula 6 and 1,1'-carbonyldiimidazole are first reacted in a dimethylformamide solvent (the reaction temperature is about 0 to 10°C, and the reaction time is 1 to 3 hours). It may be, but is not particularly limited to), after reacting the compound represented by the formula (7), it is possible to prepare a compound represented by the formula (1').

In the compound represented by Chemical Formula 1, a compound in which p is an integer of 0, as shown in Reaction Scheme 2 below,

Reacting the compound represented by Formula 8 with the compound represented by Formula 9 to prepare a compound represented by Formula 10 (step 1); And

Preparing a compound represented by Formula 1'' by reacting the compound represented by Formula 10 with the compound represented by Formula 11 prepared in Step 1 (Step 2); It can be manufactured through.

[Scheme 2]

(In Scheme 2 above,

X, R ¹ , E ¹ , E ² , E ³ , G ¹ and G ² are as defined in Formula 1).

Another aspect of the invention,

It provides a pharmaceutical composition for the prevention or treatment of kinase-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

In this case, the kinase is ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK, MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCFDPK1, , PLK4, RIPK1, RIPK5, TRKA, TRKB and TXK may be one or more kinase selected from the group consisting of.

In one aspect, the kinase-related disease,

Diseases/disorders that can be at least partially regulated by the production of programmed necrosis, apoptosis or inflammatory cytokines, especially inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment (and degeneration), retinitis pigmentosa , Macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, gout, childhood idiopathic arthritis (systemic onset pediatric idiopathic arthritis (SoJIA)), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome , Systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver injury/disease (non-alcoholic steatohepatitis, alcoholic hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen Toxicity, hepatotoxicity), kidney injury/damage (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP) , Transplant rejection (rejection of transplant organs, tissues and cells), ischemic reperfusion injury of parenchymal organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), burns, multiple sclerosis, type I diabetes , Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), tobacco smoke-induced injury, cystic fibrosis , Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), neoplastic tumors, periodontitis, NEMO-mutations (mutations of the NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), in particular NEMO-deficiency Syndrome, HOIL-1 deficiency (also known as RBCK1) Heme-oxidized IRP2 ubiquitin ligase- 1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, blood and parenchymal organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and Mycobacterium (tuberculosis)), and lysosomal storage diseases (In particular, Gaucher's disease, and GM2 gangliosidosis, alpha-mannoside accumulation, aspartylglucosamineuria, cholesteryl ester accumulation disease, chronic hexosaminidase A deficiency, cystine accumulation, Danon's disease, Fabry disease, Faber's disease, fucoside accumulation, galactosylosis, GM1 gangliosidosis, mucolipidemia, infant free sialic acid accumulation disease, pediatric hexosaminidase A deficiency, Krabe's disease, lysosome acid lipase deficiency, inflammatory white matter Dystrophy, mucopolysaccharide disorder, multiple sulfatate deficiency, Niemann-Pick disease, neuroseroid lipofuscinosis, Pompe disease, adenomyosis, Sandhoff disease, Schindler's disease, sialic acid accumulation disease, Tay-Sax and Wall Panacea), Stevens-Johnson syndrome, glaucoma, spinal cord injury, pancreatic duct adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, acute liver failure, and the like.

The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. Also, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used as diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents, suspension solvents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

The pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. How to do.

At this time, in order to formulate a formulation for parenteral administration, a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and it is administered in ampoules or vials. Can be produced. The composition may be sterile and/or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, conventional methods of mixing, granulation It can be formulated according to the chemical or coating method.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycols). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and, if desired, a boron such as starch, agar, alginic acid or its sodium salt, etc. It may contain an releasing or boiling mixture and/or absorbent, colorant, flavoring agent, and sweetening agent.

The pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or in combination with other anticancer drugs in use. Can.

Another aspect of the invention,

Provides a health functional food composition for preventing or improving kinase-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient,

At this time, the kinase is ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK, MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1 It may be one or more kinase selected from the group consisting of PIKFYVE, PLK4, RIPK1, RIPK5, TRKA, TRKB and TXK.

Since the kinase-related disease is the same as described above, a detailed description is omitted to avoid overlapping explanation.

The compound represented by Formula 1 according to the present invention may be added as it is to foods or used with other foods or food ingredients, and may be suitably used according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to its purpose of use (for prevention or improvement). In general, the amount of the compound in the health food can be added to 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene purposes or for health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components except for containing the compound as an essential component in the indicated proportions, and may contain various flavors or natural carbohydrates, etc., as additional components, such as ordinary beverages. have. Examples of the natural carbohydrates described above include monosaccharides, such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, etc.; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g per 100 g of the composition of the present invention, preferably about 5 to 12 g.

Furthermore, in addition to the above, the compound represented by Chemical Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents, and flavoring agents such as natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.

Another aspect of the present invention is the step of administering the benzo[b][1,4]oxazepine derivative, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof, to a subject in need thereof It provides a method for treating a kinase-related disease, including.

Another aspect of the present invention, for use in the prevention or treatment of kinase-related diseases, the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, or pharmaceutically acceptable salts thereof to provide.

Another aspect of the present invention, for use in the manufacture of a medicament for use in the prevention or treatment of kinase-related diseases, the benzo[b][1,4]oxazepine derivatives, stereoisomers thereof, hydrates thereof, Or the use of a pharmaceutically acceptable salt thereof.

The benzo[b][1,4]oxazepine derivatives provided in one aspect of the present invention are ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK , MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1, PIKFYVE, PLK4, RIPK1, RIPK5, TRKA, exhibits excellent inhibitory activity against one or more kinases selected from the group consisting of TRK and kinase-related diseases There is an effect that can be used as a therapeutic agent, which is supported by experimental examples described below.

Hereinafter, the present invention will be described in detail by examples and experimental examples.

However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited thereto.

The compound synthesized in the Examples of the present invention was purified or structural analysis was performed by the following HPLC conditions: medium pressure liquid chromatography (MPLC); For medium pressure liquid chromatography, CombiFlash Rf + UV from TELEEDYNE ISCO was used.

For analysis HPLC Condition ( ACQUITY UPLC H-Class Core System)

The equipment equipped with mass QDA Detector manufactured by Waters was used for UPLC sytem (ACQUITY UPLC PDA Detector) manufactured by Waters. The column used was ACQUITY UPLC®BEH C18 from Water (1.7,㎛, 2.1X50 mm), and the column temperature was performed at 30°C.

Mobile phase A used water containing 0.1% formic acid and mobile phase B used acetonitrile containing 0.1% formic acid.

Gradient condition (3 minutes at 10-100% B, moving speed = 0.6ml/min)

Tablet Prep- LCMS (Preparative-Liquid chromatography mass spectrometry)

The equipment equipped with mass QDA Detector manufactured by Waters was used for the Autopurification HPLC sytem (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) manufactured by Waters. The column used was SunFire® Prep C18 OBD ^TM (5 μm, 19×50 mm) from Water, and the column temperature was performed at room temperature.

Mobile phase A used water containing 0.035% trifluoroacetic acid, and mobile phase B used methanol containing 0.035% trifluoroacetic acid.

Gradient condition (15-100% B for 10 minutes, moving speed=25ml/min)

Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)

Waters manufactured equipment was used in Prep 150 LC sytem (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III) manufactured by Waters. The column used was XTERRA®Prep RP18 OBD ^TM (10 μm, 30X300 mm) from Water, and the column temperature was performed at room temperature.

Gradient condition (120 minutes at 3-100% B, moving speed = 40ml/min)

The commercial reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 20 to 25°C. For concentration under reduced pressure or removal of solvent, a rotary evaporator was used.

< Manufacturing example 1> (R)-3-amino-5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine -4(5H)-one manufacturing

Step 1: N-( tert - Butoxycarbonyl )-O-(2- Nitrophenyl )- Preparation of D-serine

After adding 60% NaH (409 mg, 10.23 mmol) to DMF (3.5 ml) and stirring at 0° C., (tert-butoxycarbonyl)-D-serine (1 g, 4.87 mmol) to DMF (3.5 ml). ) Was added slowly and stirred for 2 hours. Then, a solution of 1-fluoro-2-nitrobenzene (756 mg, 5.36 mmol) dissolved in DMF (3.5 ml) was slowly added to the reaction mixture, followed by stirring at 0°C for 3 hours. Distilled water was added to the reaction mixture at 0°C, stirred, and ethyl acetate was added. The reaction mixture was acidified to pH 5.0 by adding 1N hydrochloric acid. This was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the target compound N-(tert-butoxycarbonyl)-O-(2-night Lophenyl)-D-serine (1.2 g, 75%) was obtained.

MS (m/z): 227.09 [M+1] ⁺ , UPLC rt (min): 1.48

Step 2: O-(2- Aminophenyl )-N-( tert - Butoxycarbonyl ))- Preparation of D-serine

Compound N-(tert-butoxycarbonyl)-O-(2-nitrophenyl)-D-serine (1.5 g, 4.60 mmol) obtained in Step 1 of Preparation Example 1 was added to methanol (50 ml), After stirring, Pd/C (150 mg) was added, followed by stirring for 2 hours while flowing hydrogen gas. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol. After concentrating the obtained filtrate, the target compound O-(2-aminophenyl)-N-(tert-butoxycarbonyl))-D-serine (1.3 g, 95%) was obtained and used in the next reaction without purification.

MS (m/z): 197.18 [M+1] ⁺ , UPLC rt (min): 1.12

Step 3: tert -Butyl(R)-(4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxozepine Preparation of 3-day carbamate

Compound O-(2-aminophenyl)-N-(tert-butoxycarbonyl))-D-serine (1.3 g, 4.39 mmol) and DIPEA (0.84 ml, 4.83 mmol) obtained in Step 2 of Preparation Example 1 above Was added to DMSO (16 ml) to dissolve, HATU (1.83 g, 4.83 mmol) was added, followed by stirring at room temperature for 30 minutes. After adding distilled water to the reaction mixture, a precipitate is formed, stirred for 15 minutes in ice water, and the solid obtained by filtration is washed with a minimum amount of distilled water and dried to obtain the desired compound tert-butyl(R)-(4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxozepin-3-yl carbamate (1.2 g, 98%) was obtained and used in the next reaction without purification.

MS (m/z): 179.12 [M+1] ⁺ , UPLC rt (min): 1.46

Step 4: tert -Butyl(R)-(5- methyl -4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepine -3-day) Preparation of carbamate

Compound tert-butyl(R)-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxozepin-3-yl carbamate obtained in Step 3 of Preparation Example 1 ( 1.2 g, 4.31 mmol) and Cs ₂ CO ₃ (1.96 g, 6.04 mmol) was added to DMF (12 ml) to dissolve, and MeI (0.32 ml, 5.17 mmol) was slowly added for 15 minutes and stirred for 16 hours while flowing nitrogen. After completion of the reaction, ice water is added to form a solid, filtered, washed with distilled water, and dried to dry the desired compound tert-butyl(R)-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)carbamate (0.93 g, 73%) was obtained and used in the next reaction without purification.

MS (m/z): 193.11 [M+1] ⁺ , UPLC rt (min): 1.57

Step 5: (R)-3-amino-5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine Preparation of -4(5H)-one

Compound tert-butyl (R)-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3- obtained in Step 4 of Preparation Example 1 1) Carbamate (0.93 g, 3.18 mmol) was added to DCM (40 ml) and dissolved, followed by stirring with 4N hydrochloric acid. The reaction mixture was concentrated under reduced pressure, purified by adding diethyl ether, filtered and dried to obtain the desired compound (R)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]. Oxazepine-4(5H)-one (0.71 g, 99%) was obtained.

MS (m/z): 193.11 [M+1] ⁺ , UPLC rt (min): 0.46

< Manufacturing example 2> (S)-3-amino-5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine -4(5H)-one manufacturing

(S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one of Preparation Example 2 was prepared in a similar manner to Preparation Example 1. It was used in the synthesis of the following examples.

MS (m/z): 193.20 [M+1] ⁺ , UPLC rt (min): 0.44

< Manufacturing example 3> (S)-3-amino-5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine -4(5H)-one manufacturing

Step 1: tert -Butyl (S)-(5- Cyclopropyl -4-oxo-2,3,4,5- Tetrahydrobene Preparation of crude [b][1,4]oxazepin-3-yl)carbamate

Compound tert-butyl (R)-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxozepin-3-yl carbamate prepared in Step 3 of Preparation Example 1 (250 mg, 0.9 mmol), DMAP (329 mg, 2.7 mmol), copper(II) acetate (32.6 mg, 0.18 mmol), cyclopropylboronic acid (154 mg, 1.8 mmol) was dissolved in toluene (12 ml). To this reaction mixture, NaHMDS (dissolved in toluene) (0.9 ml, 0.90 mmol) was added and reacted for 16 hours at 95° C. After the reaction was cooled to room temperature, the mixture was added to 0.5N HCl aq. (35 ml) to terminate the reaction. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (hexane/ethyl acetate) to obtain a target compound as a solid (180 mg, 63%).

Step 2: (S)-3-amino-5- Cyclopropyl -2,3- Dihydrobenzo[b][1,4]oxazepine Preparation of -4(5H)-circle

Compound tert-butyl (S)-(5-cyclopropyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine prepared in Step 1 of Preparation Example 3- 3-Day) Carbamate (60 mg, 0.19 mmol) was dissolved in DCM (1.5 ml) and stirred while adding 4N HCl (0.8 ml, 3.2 mmol). The reaction mixture was concentrated under reduced pressure, added to diethyl ether to solidify, filtered and dried to obtain the target compound (S)-3-amino-5-cyclopropyl-2,3-dihydrobenzo[b][1,4]. Oxazepine-4(5H)-one (47.9 mg, 100%) was obtained.

< Manufacturing example 4> (S)-3,7-amino-5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine -4(5H)-one manufacturing

Step 1: N-( tert - Butoxycarbonyl )-O-(4-( Methoxycarbonyl )-2- Nitrophenyl )- Preparation of L-serine

After adding 60% NaH (409 mg, 10.23 mmol) to DMF (3.5 ml) and stirring at 0° C., (tert-butoxycarbonyl)-L-serine (1 g, 4.87 mmol) was added to DMF (3.5 ml). ) Was added slowly and stirred for 2 hours. Then, a solution of methyl 4-fluoro-3-nitrobenzoate (1.07 g, 5.36 mmol) dissolved in DMF (3.5 ml) was slowly added to the reaction mixture, followed by stirring at 0°C for 3 hours. Distilled water was added to the reaction mixture at 0°C, stirred, and ethyl acetate was added. The reaction mixture was acidified to pH 5.0 by adding 1N hydrochloric acid. This was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the target compound N-(tert-butoxycarbonyl)-O-(4-( Methoxycarbonyl)-2-nitrophenyl)-L-serine (1.4 g, 75%) was obtained.

Step 2: O-(2-amino-4-( Methoxycarbonyl )Phenyl)-N-( tert - Butoxycarbonyl )- Preparation of L-serine

Compound N-(tert-butoxycarbonyl)-O-(4-(methoxycarbonyl)-2-nitrophenyl)-L-serine (1.5 g, 4.60 mmol) obtained in Step 1 of Preparation Example 4 above Was added to methanol (50 ml) and stirred, Pd/C (150 mg) was added, followed by stirring for 2 hours while flowing hydrogen gas. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol. After concentrating the obtained filtrate, the target compound O-(2-amino-4-(methoxycarbonyl)phenyl)-N-(tert-butoxycarbonyl)-L-serine (1.3 g, 95%) was obtained and used in the next reaction without purification. .

Step 3: methyl (S)-3-(( tert - Butoxycarbonyl )Amino)-4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepine -Preparation of 7-carboxylate

Compound O-(2-amino-4-(methoxycarbonyl)phenyl)-N-(tert-butoxycarbonyl)-L-serine (1.3 g, 4.39 mmol) obtained in Step 2 of Preparation Example 4 and After adding and dissolving DIPEA (0.84 ml, 4.83 mmol) in DMSO (16 ml), HATU (1.83 g, 4.83 mmol) was added, followed by stirring at room temperature for 30 minutes. After adding distilled water to the reaction mixture, when a precipitate is formed, it is stirred for 15 minutes in ice water, and the solid obtained by filtration is washed with a minimum amount of distilled water and dried to obtain the desired compound methyl(S)-3-((tert-butoxycarbonyl )Amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (1.2 g, 98%) was obtained. Used.

Step 4: methyl (S)-3-(( tert - Butoxycarbonyl )Amino)-5- methyl -4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepine -Preparation of 7-carboxylate

Compound methyl (S)-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, obtained in Step 3 of Preparation Example 4 above 4]oxazepine-7-carboxylate (1.2 g, 4.31 mmol) and Cs ₂ CO ₃ (1.96 g, 6.04 mmol) was added to DMF (12 ml) to dissolve, and MeI (0.32 ml, 5.17 mmol) was slowly added for 15 minutes and stirred for 16 hours while flowing nitrogen. After completion of the reaction, ice water is added to form a solid, filtered, washed with distilled water, and dried to obtain the desired compound methyl(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (0.93 g, 73%) was obtained and used in the next reaction without purification.

Step 5: (S)-3-(( tert - Butoxycarbonyl )Amino)-5- methyl -4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepine Preparation of -7-carboxylic acid

Compound methyl (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] obtained in Step 4 of Preparation Example 4 ][1,4]oxazepine-7-carboxylate (500 mg, 1.427 mmol) was dissolved in THF (16 ml)/water (5 ml), and LiOH (2.141 ml, 2.141 mmol) was dissolved in water (1.0 ml). Dissolve in and add to the reaction mixture. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was added to ice water (70 ml) to terminate the reaction and washed with ethyl acetate. The aqueous layer was acidified to pH ~3, extracted several times with ethyl acetate, and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (S)-3-((tert-butoxycarbonyl)amino)-5-methyl- 4-Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (456 mg, 90%) was obtained and used in the next reaction without purification.

Step 6: die - tert -Butyl (5- methyl -4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepine Preparation of -3,7-diyl)(S)-dicarbamate

Compound (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] prepared in Step 5 of Preparation Example 4 ][1,4]oxazepine-7-carboxylic acid (78 mg, 0.232 mmol), DPPA (0.070 ml, 0.325 mmol), TEA (0.091 ml, 0.649 mmol), tBuOH (0.439 ml, 4.59 mmol) dissolved in toluene Then, the mixture was stirred at 70°C for 30 minutes and stirred at 100°C for 16 hours. After confirming that the reaction was over, the mixture was slowly cooled to room temperature, the solvent was concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the desired compound di-tert-butyl (5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3,7-diyl)(S)-dicarbamate was obtained.

Step 7: (S)-3,7- Diamino -5- methyl -2,3- Dihydrobenzo[b][1,4]oxazepine Preparation of -4(5H)-raw hydrochloride

Compound di-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3,7 prepared in Step 6 of Preparation Example 4 above -Diyl)(S)-Dicarbamate (75 mg, 0.184 mmol) was dissolved in DCM (1.5 ml), followed by HCl (0.782 ml, 3.13 mmol). The reaction mixture was stirred at room temperature for 16 hours, the solvent was concentrated under reduced pressure, solidified while adding to diethyl ether, filtered and dried to obtain the target compound (S)-3,7-diamino-5-methyl-2,3- Dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride was obtained.

< Example 1> (S)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylphenyl )-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea production

step 1: 3 - ((Trimethylsilyl)ethynyl)imidazo [1,2-b] Pyridazine Produce

3-Bromoimidazo[1,2-b]pyridazine (10 g, 50.5 mmol), Pd(PPh ₃ ) ₄ (2.92 g, 2.52 mmol) and CuI (0.962 g, 5.05 mmol) were added and acetonitrile was added. (50.5 ml) was added and diluted, and then nitrogen was flowed and sonicated for 5 minutes to remove gas. Trimethylsilylacetylene (7.44 g, 76 mmol) and triethylamine (28.2 ml, 202 mmol) were added to the reaction mixture, followed by reaction at 80°C for 1 hour. After the reaction, the reaction mixture was filtered through celite, and the filtrate obtained was concentrated under reduced pressure using a rotary evaporator, followed by 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (11 g, 101 %), and used for the next reaction without purification.

MS (m/z): 216. 15[M+1] ⁺ , UPLC rt (min): 1.63

step 2: 3 - Of ethynyl imidazo[1,2-b]pyridazine Produce

Compound 3-((trimethylsilyl)ethynyl)imidazo[1,2-b]pyridazine (11 g, 51.1 mmol) and K ₂ CO ₃ (21.18 g, 153 mmol) obtained in Step 1 of Example 1 above Was added to methanol (51.1 ml) and dissolved, followed by stirring for 1 hour. After the reaction, the reaction mixture was filtered and the filtrate obtained was concentrated under reduced pressure using a rotary evaporator, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a solid target compound 3-ethynylimidazo[1 ,2-b]pyridazine (5.78 g, 80%).

MS (m/z): 144.03 [M+1] ⁺ , UPLC rt (min): 0.87

step 3: 3 -( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylaniline Produce

Compound 3-ethynylimidazo[1,2-b]pyridazine (400 mg, 2.79 mmol), 3-iodo-4-methylaniline (715 mg, 3.07 mmol) obtained in Step 2 of Example 1 above Was added to ethyl acetate (9.3 ml), dissolved and sonicated for 5 minutes while flowing nitrogen. Pd(PPh ₃ ) ₄ (161 mg, 0.140 mmol), CuI (53.2 mg, 0.279 mmol) and DIPEA (976 μl, 5.59 mmol) were added to the reaction mixture, followed by stirring at 50° C. for 2 hours. The reaction mixture was filtered through celite, and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a target compound of solid 3-(imidazo[1,2-b]pyridazine-3-ylethynyl). 4-methylaniline (555 mg, 80%) was obtained.

MS (m/z): 249.16 [M+1] ⁺ , UPLC rt (min): 1.12

Step 4: (S)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylphenyl )-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) Preparation of urea

Compound 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylaniline (70 mg, 0.282 mmol) obtained in Step 3 of Example 1 was added to DMF (2 ml). After adding and dissolving, DIPEA (0.11 ml, 1.41 mmol) was added and stirred for 10 minutes. And CDI (91 mg, 0.564 mmol) was added and stirred for 2 hours, and the compound (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1, obtained in Preparation Example 2 was added. 4] Oxazepine-4(5H)-one (108 mg, 0.564 mmol) was added and stirred for 2 hours. After the reaction, the reaction mixture was washed with ethyl acetate and distilled water, the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified using a Prep-150 device, and then the target compound (S)-1-(3-(imidazo[1, 2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa Gepin-3-yl)urea (132 mg, 40%) was obtained.

MS (m/z): 467.26 [M+1] ⁺ , UPLC rt (min): 1.54

< Example 2> (R)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylphenyl )-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea production

Step 1: (R)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylphenyl )-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl) Preparation of urea

Compound 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylaniline (100 mg, 0.403 mmol) obtained in Step 3 of Example 1 was added to DMF (2 ml). After addition and dissolution, pyridine (0.16 ml, 2.01 mmol) was added and stirred for 10 minutes. And CDI (131 mg, 0.806 mmol) was added and stirred for 2 hours, and the compound (R)-3-amino-5-methyl-2,3-dihydrobenzo[b][1, obtained in Preparation Example 1 was added. 4] Oxazepine-4(5H)-one (155 mg, 0.806 mmol) was added and stirred for 2 hours. After the reaction, the reaction mixture was washed with ethyl acetate and distilled water, the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified using a Prep-150 device, and then the target compound (R)-1-(3-(imidazo[1, 2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa Gepin-3-yl)urea (35 mg, 19%) was obtained.

MS (m/z): 467.26 [M+1] ⁺ , UPLC rt (min): 1.61

< Example 3> (S)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )Phenyl)-3-(5- Me Preparation of butyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea

step 1: 3 -( Imidazo[1,2-b]pyridazine -3- Ilethynyl ) Preparation of aniline

Compound 3-ethynylimidazo[1,2-b]pyridazine (1 g, 6.99 mmol), 3-iodoaniline (0.92 ml, 7.68 mmol) obtained in Step 2 of Example 1 above is ethyl acetate ( 35 ml), dissolved and sonicated for 5 minutes while flowing nitrogen. Pd(PPh ₃ ) ₄ (404 mg, 0.349 mmol), CuI (133 mg, 0.699 mmol) and DIPEA (2.44 ml, 14 mmol) were added to the reaction mixture, followed by stirring at 50° C. for 2 hours. The reaction mixture was filtered through celite, and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain a target compound of solid 3-(imidazo[1,2-b]pyridazine-3-ylethynyl). Aniline (1.6 g, 98%) was obtained.

MS (m/z): 235.13 [M+1] ⁺ , UPLC rt (min): 1.16

Step 2: (S)-1-(3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )Phenyl)-3-(5- methyl Preparation of -4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea

Compound 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)aniline (100 mg, 0.437 mmol) obtained in Step 1 of Example 3 was added to DMF (2 ml) and dissolved therein. , pyridine (0.08 ml, 1.067 mmol) was added and stirred for 10 minutes. And CDI (90 mg, 0.555 mmol) was added and stirred for 2 hours, and the compound (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1] obtained in Preparation Example 2 was added. 4] Oxazepine-4(5H)-one (146 mg, 0.640 mmol) was added and stirred for 2 hours. After the reaction, the reaction mixture was washed with ethyl acetate and distilled water, the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified using a Prep-150 device, and then the target compound (S)-1-(3-(imidazo[1, 2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3 -Day) urea (64 mg, 27%).

MS (m/z): 453.31 [M+1] ⁺ , UPLC rt (min): 1.49

Examples 4 to 40 were prepared in a similar manner to Example 1, and the compound names, chemical structural formulas, and UPLC analysis results of Examples 1 to 40 are summarized in Table 1 below.

Example rescue Compound name MASS UPLC
rt (min) One

(S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate 467.26
[M+1] ⁺ 1.54 2

(R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate 467.26
[M+1] ⁺ 1.61 3

(S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate 453.31
[M+1] ⁺ 1.49 4

(R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4,5- Tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate 453.31
[M+1] ⁺ 1.49 5

(S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3-(imidazo [1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate 480.19 6

(R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3-(imidazo [1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate 480.19 7

(S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3-(imidazo [1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate 452.16 8

(R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3-(imidazo [1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate 452.16 9

Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate 510.14 10

Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate 510.17 11

(R)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 467.17 12

(S)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 467.17 13

(R)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 530.07 14

(S)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 530.07 15

(R)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 470.15 16

(S)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 470.15 17

Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate 510.17 18

Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate 510.17 19

(R)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 467.17 20

(S)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 467.17 21

(R)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 530.07 22

(S)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 530.07 23

(R)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 470.15 24

(S)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-( 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 470.15 25

(S)-1-(5,7-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 466.18 26

(S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(7-methoxy-5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 482.17 27

(S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4,5- Tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)urea 453.15 28

(S)-1-(5-cyclopropyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3-(already Dazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea 478.18 29

(S)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 470.15 30

(R)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 470.15 31

(S)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 470.15 32

(R)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 470.15 33

(S)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 488.14 34

(R)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 488.14 35

(S)-1-(2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15 36

(R)-1-(2-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15 37

(S)-1-(5-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15 38

(R)-1-(5-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15 39

(S)-1-(4-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15 40

(R)-1-(4-(imidazo[1,2-b]pyridazine-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea 453.15

< Example 41> (S)-3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- methyl -N-(5- methyl Preparation of -4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide

step 1: 3 -( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- Methylbenzoic acid Produce

Compound 3-ethynylimidazo[1,2-b]pyridazine (400 mg, 2.79 mmol), 3-iodo-4-methylbenzoic acid (715 mg, 3.07 mmol) obtained in Step 2 of Example 1 above Was added to ethyl acetate (9.3 ml), dissolved and sonicated for 5 minutes while flowing nitrogen. Pd(PPh ₃ ) ₄ in the reaction mixture (161 mg, 0.140 mmol), CuI (53.2 mg, 0.279 mmol) and DIPEA (976 μl, 5.59 mmol) were added and stirred at 50° C. for 2 hours. The reaction mixture was filtered through celite, and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and then purified by medium pressure liquid chromatography (diclomethane/ethyl acetate) to obtain the target compound 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4 -Methylaniline (555 mg, 80%).

MS (m/z): 278.11 [M+1] ⁺ , UPLC rt (min): 1.36

Step 2: (S)-3-( Imidazo[1,2-b]pyridazine -3- Ilethynyl )-4- methyl -N-(5- methyl Preparation of -4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide

Compound 3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylbenzoic acid (50 mg, 0.18 mmol) and COMU (93 mg, 0.216) obtained in Step 1 of Example 25 above. mmol DIPEA (0.126 ml, 0.72 mmol) was added to DMF (1 ml) and stirred for 5 minutes, and compound (S)-3-amino-5-methyl-2,3-dihydro obtained in Preparation Example 2 above Benzo[b][1,4]oxazepine-4(5H)-one (34 mg, 0.18 mmol) was added and stirred for 2 hours After completion of the reaction, extraction was performed with ethyl acetate and brine to combine the organic layers. After drying with sodium sulfate, concentrated under reduced pressure, purified using a Prep-150 device, and then the target compound (S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl- N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide (63 mg, 77%) was obtained.

MS (m/z): 452.25 [M+1] ⁺ , UPLC rt (min): 1.56

Examples 42 to 44 were prepared in a similar manner to Example 41, and the compound names, chemical structural formulas, and UPLC analysis results of Examples 41 to 44 are summarized in Table 2 below.

Example rescue Compound name MASS UPLC
rt (min) 41

(S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetra Hydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trichloroacetate 452.25
[M+1] ⁺ 1.56 42

(R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4,5-tetra Hydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trichloroacetate 452.25
[M+1] ⁺ 1.55 43

(S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)benzamide 438.31
[M+1] ⁺ 1.54 44

(R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b ][1,4]oxazepin-3-yl)benzamide 438.26
[M+1] ⁺ 1.53

< Experimental Example 1> Evaluation of various kinase inhibitory activities of compounds according to the present invention

The following experiment was performed to evaluate the inhibitory activity of the compound according to the present invention for more enzymes.

Specifically, among the example compounds of the present invention, the selected examples 3, 4, and 32 were commissioned by DiscovreX to measure enzyme selectivity, and experiments were performed using a panel for scanMAX ^TM Kinase analysis. Proceeded.

At this time, the concentration of the drug to be treated with enzyme was 1 μM in DMSO, the control percentage (% control) was determined in the same manner as in Formula 1 below, and the results are shown in Table 3 below.

[Equation 1]

(Example compound-positive control) / (negative control-positive control) x 100

Here, the positive control refers to a compound showing a control percentage of 0%, and the negative control shows a control percentage of 100% with DMSO. In addition, the enzyme selectivity of the present invention was judged to have activity against the enzyme if the control percentage for each enzyme is <35% (ie less than 35%).

Example 3 Example 4 Example 44 AAK1 96 76 74 ABL1(E255K)-phosphorylated 89 79 21 ABL1(F317I)-nonphosphorylated 97 100 0 ABL1(F317I)-phosphorylated 100 100 43 ABL1(F317L)-nonphosphorylated 46 94 0 ABL1(F317L)-phosphorylated 46 93 8.2 ABL1(H396P)-nonphosphorylated 17 67 0.1 ABL1(H396P)-phosphorylated 86 85 15 ABL1(M351T)-phosphorylated 98 96 21 ABL1(Q252H)-nonphosphorylated 62 67 0 ABL1(Q252H)-phosphorylated 100 100 36 ABL1(T315I)-nonphosphorylated 67 99 0.15 ABL1(T315I)-phosphorylated 82 91 62 ABL1(Y253F)-phosphorylated 100 100 53 ABL1-nonphosphorylated 28 48 0.1 ABL1-phosphorylated 56 70 10 ABL2 83 99 6.2 ACVR1 100 100 100 ACVR1B 100 100 75 ACVR2A 75 100 95 ACVR2B 73 100 80 ACVRL1 100 78 93 ADCK3 100 83 100 ADCK4 100 63 100 AKT1 48 96 93 AKT2 100 92 100 AKT3 100 98 98 ALK 100 100 99 ALK(C1156Y) 86 93 75 ALK(L1196M) 92 96 99 AMPK-alpha1 100 84 95 AMPK-alpha2 100 63 73 ANKK1 84 86 45 ARK5 100 81 100 ASK1 100 100 100 ASK2 100 83 100 AURKA 100 61 83 AURKB 57 2.9 21 AURKC 70 54 61 AXL 100 85 66 BIKE 95 100 94 BLK 67 100 100 BMPR1A 100 100 84 BMPR1B 100 100 95 BMPR2 100 100 82 BMX 100 81 70 BRAF 90 81 79 BRAF(V600E) 50 94 75 BRK 100 87 91 BRSK1 100 93 100 BRSK2 100 86 84 BTK 97 100 94 BUB1 100 84 100 CAMK1 100 94 88 CAMK1B 89 97 93 CAMK1D 99 89 94 CAMK1G 100 88 91 CAMK2A 100 100 93 CAMK2B 100 100 94 CAMK2D 100 90 96 CAMK2G 100 78 91 CAMK4 88 72 83 CAMKK1 100 90 90 CAMKK2 100 85 90 CASK 94 96 92 CDC2L1 100 68 100 CDC2L2 97 100 95 CDC2L5 89 83 77 CDK11 12 47 7 CDK2 100 100 96 CDK3 100 98 100 CDK4 100 88 97 CDK4-cyclinD1 100 100 83 CDK4-cyclinD3 100 100 90 CDK5 100 79 95 CDK7 60 75 74 CDK8 3.5 44 0 CDK9 100 74 100 CDKL1 99 96 91 CDKL2 14 65 55 CDKL3 43 92 97 CDKL5 100 100 100 CHEK1 100 100 100 CHEK2 86 94 100 CIT 55 79 100 CLK1 80 82 94 CLK2 100 99 94 CLK3 73 90 100 CLK4 100 100 100 CSF1R 96 76 60 CSF1R-autoinhibited 100 68 100 CSK 100 100 94 CSNK1A1 96 66 0 CSNK1A1L 100 100 99 CSNK1D 100 100 89 CSNK1E 80 88 99 CSNK1G1 98 100 100 CSNK1G2 99 96 97 CSNK1G3 92 95 96 CSNK2A1 100 100 97 CSNK2A2 100 83 90 CTK 100 100 100 DAPK1 85 97 88 DAPK2 98 100 95 DAPK3 100 100 96 DCAMKL1 100 59 96 DCAMKL2 100 98 98 DCAMKL3 100 79 69 DDR1 0.1 26 0.05 DDR2 1.7 11 0 DLK 100 77 69 DMPK 100 100 100 DMPK2 100 93 100 DRAK1 100 91 100 DRAK2 100 94 99 DYRK1A 100 86 63 DYRK1B 91 100 99 DYRK2 100 100 100 EGFR 100 100 96 EGFR (E746-A750del) 86 100 77 EGFR(G719C) 99 97 94 EGFR(G719S) 100 98 93 EGFR (L747-E749del, A750P) 100 100 93 EGFR (L747-S752del, P753S) 62 100 56 EGFR(L747-T751del,Sins) 96 93 75 EGFR(L858R) 100 100 92 EGFR(L858R,T790M) 100 98 100 EGFR(L861Q) 92 82 63 EGFR (S752-I759del) 94 85 87 EGFR(T790M) 99 97 100 EIF2AK1 100 100 94 EPHA1 100 93 98 EPHA2 100 86 94 EPHA3 100 100 96 EPHA4 100 94 92 EPHA5 100 90 97 EPHA6 100 83 100 EPHA7 100 96 99 EPHA8 100 100 90 EPHB1 100 90 100 EPHB2 100 89 89 EPHB3 100 76 100 EPHB4 100 83 100 EPHB6 100 84 76 ERBB2 84 83 98 ERBB3 92 88 89 ERBB4 92 96 62 ERK1 100 96 98 ERK2 100 85 98 ERK3 100 97 100 ERK4 100 63 100 ERK5 95 51 100 ERK8 84 79 95 ERN1 100 81 100 FAK 82 95 86 FER 100 91 98 FES 100 82 100 FGFR1 95 96 59 FGFR2 100 96 90 FGFR3 100 91 89 FGFR3 (G697C) 100 94 89 FGFR4 100 91 100 FGR 100 81 100 FLT1 100 100 83 FLT3 13 73 38 FLT3(D835H) 83 91 96 FLT3(D835V) 100 46 65 FLT3(D835Y) 91 92 86 FLT3(ITD) 56 100 67 FLT3(ITD,D835V) 100 75 72 FLT3(ITD,F691L) 89 0 92 FLT3(K663Q) 43 75 75 FLT3(N841I) 31 88 72 FLT3(R834Q) 100 95 77 FLT3-autoinhibited 100 90 100 FLT4 86 100 100 FRK 93 85 94 FYN 97 92 100 GAK 100 93 98 GCN2(Kin.Dom.2,S808G) 88 56 100 GRK1 99 77 100 GRK2 100 92 90 GRK3 100 78 85 GRK4 100 81 98 GRK7 100 96 72 GSK3A 78 72 87 GSK3B 98 94 100 HASPIN 85 96 90 HCK 100 70 96 HIPK1 87 68 100 HIPK2 100 88 70 HIPK3 100 100 100 HIPK4 17 64 61 HPK1 89 100 100 HUNK 74 93 59 ICK 97 100 100 IGF1R 100 100 98 IKK-alpha 100 84 99 IKK-beta 100 97 100 IKK-epsilon 100 100 76 INSR 96 90 99 INSRR 100 95 100 IRAK1 100 89 20 IRAK3 84 95 84 IRAK4 100 96 93 ITK 100 99 98 JAK1 (JH1domain-catalytic) 99 87 100 JAK1 (JH2domain-pseudokinase) 77 46 100 JAK2 (JH1domain-catalytic) 100 94 83 JAK3 (JH1domain-catalytic) 100 79 92 JNK1 100 84 91 JNK2 100 92 93 JNK3 100 93 89 KIT 32 59 25 KIT(A829P) 100 100 95 KIT(D816H) 93 100 85 KIT(D816V) 98 84 99 KIT(L576P) 54 37 32 KIT(V559D) 17 60 14 KIT(V559D,T670I) 95 89 100 KIT(V559D,V654A) 98 99 100 KIT-autoinhibited 100 86 100 LATS1 100 98 97 LATS2 100 96 100 LCK 99 83 74 LIMK1 100 100 71 LIMK2 100 100 95 LKB1 99 91 100 LOK 18 71 54 LRRK2 100 100 100 LRRK2(G2019S) 100 100 96 LTK 48 77 63 LYN 99 95 90 LZK 100 100 85 MAK 100 88 99 MAP3K1 100 100 100 MAP3K15 95 90 89 MAP3K2 100 96 93 MAP3K3 100 77 79 MAP3K4 100 95 69 MAP4K2 100 92 100 MAP4K3 100 97 88 MAP4K4 63 99 82 MAP4K5 71 100 83 MAPKAPK2 100 100 100 MAPKAPK5 100 100 100 MARK1 100 92 70 MARK2 100 100 100 MARK3 100 75 100 MARK4 100 79 76 MAST1 100 82 86 MEK1 100 87 100 MEK2 97 80 100 MEK3 100 86 86 MEK4 97 98 93 MEK5 69 74 69 MEK6 100 87 100 MELK 100 84 94 MERTK 88 100 90 MET 92 97 85 MET(M1250T) 98 100 95 MET(Y1235D) 72 83 77 MINK 95 72 66 MKK7 99 85 96 MKNK1 95 79 75 MKNK2 0.2 1.4 64 MLCK 91 97 96 MLK1 58 97 95 MLK2 79 66 78 MLK3 97 82 91 MRCKA 95 100 100 MRCKB 100 99 93 MST1 94 80 98 MST1R 98 82 100 MST2 81 63 98 MST3 88 98 93 MST4 100 100 93 MTOR 100 62 99 MUSK 49 95 93 MYLK 98 73 91 MYLK2 100 95 80 MYLK4 100 95 100 MYO3A 100 77 79 MYO3B 100 100 86 NDR1 100 70 88 NDR2 100 95 68 NEK1 100 100 99 NEK10 91 81 86 NEK11 100 74 93 NEK2 100 82 99 NEK3 85 55 100 NEK4 100 94 91 NEK5 100 98 100 NEK6 100 88 97 NEK7 100 90 98 NEK9 98 98 100 NIK 100 100 100 NIM1 100 98 100 NLK 100 85 78 OSR1 100 100 100 p38-alpha 100 97 98 p38-beta 100 100 85 p38-delta 88 75 95 p38-gamma 0.65 54 86 PAK1 100 84 93 PAK2 93 98 84 PAK3 30 74 63 PAK4 100 95 92 PAK6 100 100 100 PAK7 94 100 85 PCTK1 100 100 97 PCTK2 90 55 100 PCTK3 76 88 99 PDGFRA 7.6 13 0.5 PDGFRB 2.2 39 0.15 PDPK1 99 88 83 PFCDPK1 (P.falciparum) 81 38 24 PFPK5 (P.falciparum) 100 75 67 PFTAIRE2 99 98 100 PFTK1 99 70 91 PHKG1 100 100 100 PHKG2 100 100 94 PIK3C2B 70 90 79 PIK3C2G 88 89 99 PIK3CA 100 96 96 PIK3CA(C420R) 94 91 99 PIK3CA(E542K) 100 71 76 PIK3CA(E545A) 87 89 98 PIK3CA(E545K) 95 70 93 PIK3CA(H1047L) 100 91 70 PIK3CA(H1047Y) 80 93 98 PIK3CA(I800L) 100 73 90 PIK3CA(M1043I) 97 93 91 PIK3CA(Q546K) 100 84 84 PIK3CB 100 69 77 PIK3CD 100 92 96 PIK3CG 100 91 95 PIK4CB 100 83 98 PIKFYVE 92 23 72 PIM1 100 100 93 PIM2 100 95 97 PIM3 99 87 93 PIP5K1A 97 99 99 PIP5K1C 83 70 75 PIP5K2B 88 100 100 PIP5K2C 96 85 96 PKAC-alpha 80 75 74 PKAC-beta 91 98 97 PKMYT1 100 99 92 PKN1 100 65 94 PKN2 99 100 92 PKNB (M.tuberculosis) 95 84 95 PLK1 100 100 100 PLK2 100 100 100 PLK3 99 84 97 PLK4 29 67 100 PRKCD 96 92 76 PRKCE 85 89 55 PRKCH 96 99 100 PRKCI 91 99 78 PRKCQ 97 66 86 PRKD1 98 86 100 PRKD2 81 78 96 PRKD3 100 100 100 PRKG1 97 100 100 PRKG2 100 100 90 PRKR 100 100 100 PRKX 93 100 100 PRP4 100 100 100 PYK2 100 78 96 QSK 80 75 82 RAF1 65 74 100 RET 100 93 91 RET(M918T) 88 100 100 RET(V804L) 94 100 100 RET(V804M) 100 100 100 RIOK1 100 100 77 RIOK2 81 96 55 RIOK3 100 100 85 RIPK1 54 74 0.45 RIPK2 88 86 72 RIPK4 100 100 100 RIPK5 100 60 20 ROCK1 100 78 91 ROCK2 100 71 100 ROS1 96 92 100 RPS6KA4 (Kin.Dom.1-N-terminal) 100 99 100 RPS6KA4 (Kin.Dom.2-C-terminal) 100 100 100 RPS6KA5 (Kin.Dom.1-N-terminal) 100 100 97 RPS6KA5 (Kin.Dom.2-C-terminal) 100 94 93 RSK1 (Kin.Dom.1-N-terminal) 100 90 100 RSK1 (Kin.Dom.2-C-terminal) 73 100 100 RSK2 (Kin.Dom.1-N-terminal) 100 83 100 RSK2 (Kin.Dom.2-C-terminal) 96 100 81 RSK3 (Kin.Dom.1-N-terminal) 95 80 89 RSK3 (Kin.Dom.2-C-terminal) 90 96 90 RSK4 (Kin.Dom.1-N-terminal) 100 100 95 RSK4 (Kin.Dom.2-C-terminal) 77 98 96 S6K1 97 87 80 SBK1 100 100 97 SGK 99 82 67 SgK110 100 70 100 SGK2 89 83 82 SGK3 100 100 68 SIK 100 90 93 SIK2 99 100 82 SLK 86 84 98 SNARK 98 100 98 SNRK 100 100 100 SRC 92 95 89 SRMS 87 91 90 SRPK1 89 100 96 SRPK2 100 100 89 SRPK3 100 89 98 STK16 91 84 100 STK33 100 100 100 STK35 100 99 88 STK36 93 100 95 STK39 100 95 94 SYK 100 66 98 TAK1 100 88 59 TAOK1 100 72 94 TAOK2 99 97 100 TAOK3 100 98 90 TBK1 90 67 87 TEC 100 98 97 TESK1 100 96 89 TGFBR1 97 88 100 TGFBR2 100 85 100 TIE1 62 88 64 TIE2 60 100 36 TLK1 70 73 94 TLK2 100 100 100 TNIK 88 65 78 TNK1 100 100 54 TNK2 99 100 100 TNNI3K 84 85 94 TRKA 44 72 17 TRKB 66 84 31 TRKC 89 98 41 TRPM6 99 98 84 TSSK1B 100 99 96 TSSK3 98 100 87 TTK 98 100 94 TXK 100 94 19 TYK2 (JH1domain-catalytic) 100 99 78 TYK2 (JH2domain-pseudokinase) 92 81 82 TYRO3 100 83 100 ULK1 100 100 100 ULK2 100 95 100 ULK3 100 82 97 VEGFR2 100 70 100 VPS34 61 47 61 VRK2 90 84 100 WEE1 60 100 84 WEE2 100 98 100 WNK1 100 80 100 WNK2 100 75 92 WNK3 100 95 100 WNK4 100 100 100 YANK1 100 92 93 YANK2 100 97 91 YANK3 100 94 100 YES 100 100 100 YSK1 85 94 100 YSK4 100 78 60 ZAK 94 97 58 ZAP70 98 98 88

As can be seen in Table 3 above,

Example compounds according to the invention are ABL1, ABL1(E255K), ABL1(F317I), ABL1(F317L), ABL1(H396P), ABL1(M351T), ABL1(Q252H), ABL1(T315I), ABL2, AURKB, AURKB , CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, FLT3(ITD,F691L), FLT3(N841I), HIPK4, IRAK1, KIT, KIT(L576P), KIT(V559D), LOK, MKNK2, p38-gamma , PAK3, PDGFRA, PDGFRB, PFCDPK1 (P.falciparum), PIKFYVE, PLK4, RIPK1, RIPK5, TRKA, it can be seen that it has a value less than 35% of the control percentage for the kinase. This indicates that the compound according to the present invention has an inhibitory activity against the enzymes listed above, from which it is suggested that it has a useful effect when used in diseases related to the enzymes listed above.

Accordingly, example compounds according to the present invention are ABL1, ABL1(E255K), ABL1(F317I), ABL1(F317L), ABL1(H396P), ABL1(M351T), ABL1(Q252H), ABL1(T315I), ABL2, AURKB , AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, FLT3(ITD,F691L), FLT3(N841I), HIPK4, IRAK1, KIT, KIT(L576P), KIT(V559D), LOK, MKNK2, p38 -gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1 (P.falciparum), PIKFYVE, PLK4, RIPK1, RIPK5, TRKA, TRKB and TXK can be usefully used as a composition for the treatment or prevention of kinase related diseases.

< Experimental Example 2> RIPK1 (Receptor- interating serine / threonine protein kinase 1) Evaluation of enzyme inhibitory ability

The following experiments were performed to evaluate the inhibitory activity of the example compounds according to the present invention for RIPK1 (Receptor-interating serine/threo nine protein kinase 1) enzyme.

Example compounds were reacted with the purified human GST-RIPK1 (1-375, signalchem) enzyme to evaluate the enzyme inhibitory ability in the following manner. As a reaction buffer, 40 mM Tris-Hcl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/mL BSA, and 0.5 uM DTT composition were used, and all the test samples were reacted on the reaction buffer. After the test, human GST-RIPK1 (1-375, 10 ng) enzyme, purified ATP (50 uM), and a specific substrate solution were reacted for 4 hours at 25°C, and then the enzyme activity was determined by in vitro ADP-Glo ^TM kinase assay (promega) It was confirmed by using. Luminoscence was measured by reacting enzymatic activity reaction solution, ADP-Glo reaction solution, and enzyme activity detection solution in a 2:2:1 ratio. Relative to the fluorescence of the vehicle control group enzymatic activity which is not treated with the compounds were calculated to inhibit enzyme activity degree of the concentration of each compound, where the enzyme activity inhibition 50% inhibition for each compound concentration of the IC ₅₀ (nM) value for which Decided. The IC ₅₀ of each compound was determined by three data sets and was obtained using Prism (version 7.01, Graphpad) software.

The results are shown in Table 4 below.

< Experimental Example 3> Evaluation of cell protection effect in apoptosis-inducing conditions

It was confirmed through MTS analysis that the compound according to the present invention exhibits a cell protective effect under apoptosis-inducing conditions according to TNF-α. The cell death-inducing factor, such as TNF-α, was induced from the outside of the cell, and cell death was induced by FADD-deficient human Jurkat T cells. . FADD-deficient Jurkat T cell lines are cultured using RPMI medium (Hyclone) containing 10% FBS, and when performing the test, each cell is 10,000 cells/well in a 96-well plate containing medium suitable for the cell line. After dispensing at a concentration, the cells were cultured at 5% CO ₂ and 37° C. for 24 hours. After that, each well was treated with TNF-a to be 40 ng, and the compounds prepared in the above example were treated with a concentration of 1 μM at the highest concentration to give a 3-fold concentration gradient, and as a solvent control group, dimethyl sulfoxide (DMSO ) Was treated at the same concentration as 0.05% (v/v) used for compound treatment. Then, each cell was cultured for 50 hours. To confirm the viability of the cells, the mixture provided in the CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega) was added to the culture medium of each cultured cell, and further cultured at 37°C for 30 minutes. Thereafter, Luminoscence fluorescence was measured. The degree of inhibition of apoptosis induction according to the treatment concentration of each compound was calculated based on the fluorescence of the cells in which the compound was not treated, and the concentration at which the inhibitory capacity was 50% was determined as an EC ₅₀ (μM) value and prism (version 7.01, GraphPad).

The results are shown in Table 4 below.

Example Enzyme IC ₅₀ (nM) I2.I Cell EC ₅₀ (nM) Example 1 158.6 41.7 Example 2 2,560 117 Example 3 13.2 94.7 Example 4 5,517 425 Example 41 4,130 307 Example 42 105.9 37.9 Example 43 1,287 12.8 Example 44 17.7 31.6

Table 4 above shows the results of measuring the cell protective effect under the apoptosis-inducing condition of each experimental compound for Jurkat T cells lacking RIPK1 enzyme activity and FADD.

As can be seen in Table 4 above,

Example compounds according to the present invention can be confirmed that the enzyme activity and cell protective effect simultaneously shows good activity. Therefore, it can be seen that the compound according to the present invention has excellent cell protective activity under the conditions of cell death induction, as confirmed in the above experiment.

Meanwhile, the compound represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following are examples of some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, and the present invention is not limited thereto.

<Formulation Example 1> Preparation of pharmaceutical formulation

1-1. Preparation of powder

500 mg of compound of formula 1

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight fabric to prepare a powder.

1-2. Preparation of tablets

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.

1-3. Preparation of capsules

500 mg of compound of formula 1

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled into a gelatin capsule to prepare a capsule.

1-4. Preparation of injection

500 mg of compound of formula 1

Suitable amount of sterile distilled water for injection

pH Adjuster

It is prepared with the above-mentioned ingredient content per ampoule (2 ml) according to the preparation method of a conventional injection.

1-5. Preparation of liquid

100 mg of compound of formula 1

Isomerized sugar 10 g

5 g of mannitol

Purified water

Each component was added to the purified water according to the manufacturing method of the conventional liquid preparation, dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed and purified water was added to adjust the total to 100 ml, followed by filling into a brown bottle. Sterilization to prepare a liquid.

Claims (10)

A compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

(In the formula 1,
X is hydrogen or halogen;
P is an integer of 0 or 1;
E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;
E ² is =CA ² -, or =N-, and A ² is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;
E ³ is =CA ³ -, or =N-, and A ³ is hydrogen, halogen, nitro, nitryl, amino, C _1-10 linear or branched alkyl, or C _1-10 linear or Branched chain alkoxy;
R ¹ is hydrogen, C _1-10 straight or branched chain alkyl, or C _3-8 cycloalkyl;
G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, C _1-10 linear or branched alkoxycarbonyl, amino, or halogen; And
G ² is =CM ² -, or =N-, and M ² is hydrogen, C _1-10 straight or branched chain alkoxycarbonyl, amino, halogen, C _1-10 straight or branched chain alkyl, or C _1-10 linear or branched alkoxy).
According to claim 1,
X is hydrogen or halogen;
P is an integer of 0 or 1;
E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;
E ² is =CA ² -, or =N-, and A ² is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;
E ³ is =CA ³ -, or =N-, and A ³ is hydrogen, halogen, nitro, nitryl, amino, C _1-5 linear or branched alkyl, or C _1-5 linear or Branched chain alkoxy;
R ¹ is hydrogen, C _1-5 straight or branched chain alkyl, or C _3-5 cycloalkyl;
G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, C _1-5 linear or branched alkoxycarbonyl, amino, or halogen; And
G ² is =CM ² -, or =N-, and M ² is hydrogen, C _1-5 linear or branched alkoxycarbonyl, amino, halogen, C _1-5 linear or branched alkyl, or C _1-5 A straight chain or branched chain alkoxy compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
X is hydrogen, or -F;
P is an integer of 0 or 1;
E ¹ is =CA ¹ -, or =N-, and A ¹ is hydrogen, -CH ₃ , or -F;
E ² is =CA ² -, or =N-, and A ² is hydrogen;
E ³ is =CA ³ -, or =N-, and A ³ is hydrogen;
R ¹ is —CH ₃ , —CH ₂ CH ₃ , or cyclopropyl;
G ¹ is =CM ¹ -, or =N-, and M ¹ is hydrogen, methoxycarbonyl, amino, or halogen; And
G ² is =CM ² -, or =N-, and M ² is hydrogen, methoxycarbonyl, amino, halogen, -CH ₃ , or -OCH ₃ A compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by Formula 1 is a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following group of compounds:
(1) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;
(2) (R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)-3-(5-methyl-4-oxo-2, 3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;
(3) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;
(4) (R)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea trifluoroacetate;
(5) (S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate;
(6) (R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methylphenyl)urea trifluoroacetate;
(7) (S)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate;
(8) (R)-1-(5-ethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3- (Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea trifluoroacetate;
(9) Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate;
(10) Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-8-carboxylate;
(11) (R)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(12) (S)-1-(8-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(13) (R)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(14) (S)-1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(15) (R)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(16) (S)-1-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(17) Methyl(R)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate;
(18) Methyl(S)-3-(3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)ureido)-5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate;
(19) (R)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(20) (S)-1-(7-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3 -(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(21) (R)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(22) (S)-1-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(23) (R)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(24) (S)-1-(7-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)- 3-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(25) (S)-1-(5,7-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3- (3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(26) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(7-methoxy-5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(27) (S)-1-(3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo-2,3,4 ,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)urea;
(28) (S)-1-(5-cyclopropyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-3-(3 -(Imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)urea;
(29) (S)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(30) (R)-1-(4-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(31) (S)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(32) (R)-1-(2-fluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(33) (S)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4 -Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(34) (R)-1-(2,4-difluoro-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)phenyl)-3-(5-methyl-4 -Oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(35) (S)-1-(2-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(36) (R)-1-(2-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-4-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(37) (S)-1-(5-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(38) (R)-1-(5-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-3-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(39) (S)-1-(4-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(40) (R)-1-(4-(imidazo[1,2-b]pyridazin-3-ylethynyl)pyridin-2-yl)-3-(5-methyl-4-oxo-2 ,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)urea;
(41) (S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trifluoroacetate;
(42) (R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(5-methyl-4-oxo-2,3,4, 5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)benzoamide trifluoroacetate;
(43) (S)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepin-3-yl)benzamide; And
(44) (R)-3-(imidazo[1,2-b]pyridazine-3-ylethynyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydro Benzo[b][1,4]oxazepin-3-yl)benzamide.
A pharmaceutical composition for the prophylaxis or treatment of a kinase-related disease comprising the compound represented by Formula 1 of claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 5,
The kinases are ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK, MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1, PIKF , RIPK1, RIPK5, TRKA, TRKB, and pharmaceutical compositions characterized in that it is at least one kinase selected from the group consisting of TXK.
The method of claim 5,
The kinase-related disease,
Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, osteoarthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, disease selected from the group consisting of cancer and periodontitis Pharmaceutical composition.
A compound represented by Formula 1 of claim 1, a stereoisomer thereof, a hydrate thereof, or a pharmacologically acceptable salt thereof, as an active ingredient, a kinase-related disease preventing or improving health functional food composition.
The method of claim 8,
The kinases are ABL1, ABL2, AURKB, AURKB, CDK8, CDK11, CDKL2, CSNK1A1, DDR1, DDR2, FLT3, HIPK4, IRAK1, KIT, LOK, MKNK2, p38-gamma, PAK3, PDGFRA, PDGFRB, PFCDPK1, PIKF , RIPK1, RIPK5, TRKA, TRKB, and health functional food composition characterized in that it is at least one kinase selected from the group consisting of TXK.
The method of claim 8,
The kinase-related disease,
Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, osteoarthritis, gout, Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome, vasculitis, Osteoarthritis, non-alcoholic steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, nephritis, celiac disease, transplant rejection, sepsis, systemic inflammatory response syndrome, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic Dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, motor neurone disease, chronic obstructive pulmonary disease, disease selected from the group consisting of cancer and periodontitis Health functional food composition.